3-(4-Amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (I), having the generic name lenalidomide, is a non-polypeptide compound that antagonizes TNFα and is thought to elevate levels of adenosine 3′,5′-cyclic monophosphate. Lenalidomide and various structural analogues are useful in the treatment of a wide range of conditions including autoimmune disease and cancer. Structurally lenalidomide is closely related to thalidomide and is well known in the prior art (e.g. see N. Jonsson, Acta Pharm. Suecica, vol. 9, pages 521-542, 1972).
U.S. Pat. No. 5,635,517 and U.S. Pat. No. 6,281,230 describe the synthesis of lenalidomide by hydrogenating 1 g of a nitro intermediate, 3-(1-oxo-4-nitro-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione, at 50 psi pressure for 6.5 hours using 0.13 g of 10% Pd/C catalyst in 200 ml of 1,4-dioxane.
The residue was crystallized from ethyl acetate and then from dioxane/ethyl acetate. The patents indicate the yield to be about 36%.
The same patents also describe the preparation of the nitro intermediate. 4-Nitro-phthalic anhydride is coupled with 2,6-dioxopiperidine-3-ammonium chloride in glacial acetic acid and sodium acetate to obtain 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-nitro-isoindoline in 54% yield. The preparation of the nitro intermediate 3-(1-oxo-4-nitro-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione follows the same reaction conditions as described, resulting in a low yield of the nitro intermediate of about 55%.
WO 2006/028964 describes processes for the preparation of substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxo-isoindolines. The process described therein for preparing lenalidomide involves the preparation of the nitro intermediate by first coupling of an L-glutamine methyl ester with methyl 2-bromomethyl-3-nitro-benzoate in acetonitrile and cyclising the resultant N-(1-oxo-4-nitro-isoindol-2-yl)-L-glutamine methyl ester. 1 g of the nitro compound is then hydrogenated with 10% Pd/C catalyst in 600 ml of methanol at 50 psi of hydrogen for 5 hours. The solid was slurried in hot ethyl acetate and dried, resulting in a yield of 51% lenalidomide.
The prior art processes described have major disadvantages, such as:    (1) the low yield of the final product;    (2) the low yield of the nitro intermediate; and    (3) the large amount of solvent used in the hydrogenation process.
These disadvantages result in the prior art processes:    (1) being hazardous; and    (2) having poor commercial viability due to the large solvent: substrate ratio and low yield of the final product lenalidomide.
It would thus be advantageous to provide a process for the preparation of lenalidomide wherein the amount of solvent used is reduced resulting in a synthetic route that is both more economical and safer than prior art processes.
Many compounds can exist in different crystalline forms or polymorphs. These forms can exhibit varying physical, chemical and spectroscopic properties. For example, certain polymorphs of a compound may be more readily soluble in particular solvents, may flow more readily, or may compress more easily than others (e.g. see P. DiMartino et al., J. Thermal Analysis, vol. 48, pages 447-458, 1997). In the case of drugs, certain solid forms may be more bioavailable than others, while others may be more stable under certain manufacturing, storage and biological conditions. This is particularly important from a regulatory standpoint, since drugs are approved by agencies such as the U.S. Food and Drug Administration only if they meet exacting purity and characterisation standards. Indeed, the regulatory approval of one polymorph of a compound, which exhibits certain solubility and physico-chemical (including spectroscopic) properties, typically does not imply the ready approval of other polymorphs of that same compound. Polymorphic forms of a compound are known in the pharmaceutical arts to affect, for example, the solubility, stability, flowability, fractability and compressibility of the compound, as well as the safety and efficacy of drug products comprising it (e.g. see K. Knapman, Modern Drug Discovery, pages 53-57, 2000). Therefore, the discovery of new polymorphs of a drug can provide a variety of advantages.
New polymorphic forms of lenalidomide and more efficient processes for preparing them can further the development of pharmaceutical formulations and may yield numerous formulation, manufacturing and therapeutic benefits.
U.S. Pat. No. 7,465,800 describes the preparation and characterisation of a number of crystalline forms of lenalidomide, specifically forms A-H. The studies described in this patent conclude that form B is the desired polymorph for use as an active pharmaceutical ingredient (API). Form B has been used in the formulation of API into drug product for clinical studies.
The preparation of pure crystalline forms of an API provides many advantages. Pure crystalline forms of an API can be used, for example, as intermediates in preparing API for clinical studies or incorporation into final dosage forms for marketing. There is thus a need for pure crystalline forms to aid the drug formulator in his task of preparing regulatory compliant API.